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Black, CJ, Drossman, DA, Talley, NJ et al. (2 more authors) (2020) Functional gastrointestinal disorders: advances in understanding and management. The Lancet. ISSN0140-6736

https://doi.org/10.1016/s0140-6736(20)32115-2

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Black et al. Page 1 of 42

Accepted for publication 19th August 2020 1

TITLE PAGE 2

Title: Functional Gastrointestinal Disorders: Advances in Understanding and Management. 3

4

Authors: Christopher J. Black MBBS (hons)1,2, Professor Douglas A. Drossman MD3, 5

Professor Nicholas J. Talley MD4, Johannah Ruddy MEd5, Professor Alexander C. Ford 6

MD1,2. 7

8

1Leeds Gastroenterology Institute, St. James’s University Hospital, Leeds, UK. 9

2Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, UK. 10

3Center for Education and Practice of Biopsychosocial Care, Drossman Gastroenterology, 11

University of North Carolina at Chapel Hill, North Carolina, USA and the Rome Foundation, 12

North Carolina, USA 13

4NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, 14

Australia, and Hunter Medical Research Institute, Lambton, NSW, Australia 15

5Center for Education and Practice of Biopsychosocial Care, DrossmanCare, Durham, North 16

Carolina, USA and the Rome Foundation, North Carolina, USA 17

18

Correspondence: Professor Alexander C. Ford 19

Leeds Gastroenterology Institute 20

Room 125 21

4th Floor 22

Bexley Wing 23

St. James’s University Hospital 24


Beckett Street 25

Leeds 26

United Kingdom 27

LS9 7TF 28

Email: [email protected] 29

Telephone: +441132684963 30

31

Keywords: pain; bloating; dyspepsia, diarrhoea; constipation 32

33

Word count: 3883 34

35

36


ABSTRACT 37

Gastrointestinal symptoms are highly prevalent, but many people who experience them will 38

have no organic explanation for their symptoms. The majority of these people will be labelled 39

as having a functional gastrointestinal disorder (FGID), such as irritable bowel syndrome, 40

functional dyspepsia, or functional constipation. These conditions affect up to 40% of people 41

at any one point in time, and two-thirds of these people will have chronic, fluctuating 42

symptoms. The pathophysiology is complex, but involves bidirectional dysregulation of 43

brain-gut interaction, via the brain-gut axis, as well as microbial dysbiosis within the gut, 44

altered mucosal immune function, visceral hypersensitivity, and abnormal gastrointestinal 45

motility. Hence, recent nomenclature refers to them as disorders of gut-brain interaction. 46

Psychological co-morbidity is common, although whether this predates, or is driven by, the 47

symptoms is not clear. Patients with FGIDs can feel stigmatised, and often a diagnosis of an 48

FGID is not communicated effectively by physicians, nor education provided. Prompt 49

identification and treatment of FGIDs is critical, because these conditions have a considerable 50

impact on healthcare systems, and society as a whole, due to repeated consultations, 51

unnecessary investigations and surgeries, prescription and over-the-counter medicine use, 52

impaired health-related quality of life, and negative effects on ability to work. Symptom-53

based criteria are used to make a diagnosis, with the judicious use of limited investigations 54

required in some patients. The general principles of treatment are based on a biopsychosocial 55

understanding, and involve management of physical symptoms, as well as psychological co-56

morbidity, if present. In the future, treatment approaches to FGIDs are likely to become more 57

personalised based not only on symptoms, but also underlying pathophysiology and 58

psychology. 59

60

61


INTRODUCTION 62

The spectrum of symptoms attributable to the gastrointestinal tract includes 63

abdominal pain, diarrhoea, constipation, bloating, fullness, nausea, and vomiting. These 64

symptoms are common to a broad range of organic pathology, including gastrointestinal 65

cancer, inflammatory bowel disease (IBD), coeliac disease, peptic ulcer, and motility 66

disorders, such as gastroparesis. However, it is well-recognised that, for a substantial number 67

of patients, investigation reveals no underlying structural abnormality to explain these 68

symptoms, which in this context are often referred to as “functional”. Functional 69

gastrointestinal disorders (FGIDs), such as irritable bowel syndrome (IBS), functional 70

dyspepsia (FD), or functional constipation, although incompletely understood, and with a 71

complex pathophysiology, account for at least one-third of referrals to gastroenterology 72

clinics. 1 Due to a combination of the pathophysiology involved, as well as the stigma of the 73

term “functional”, these conditions have been redefined as disorders of gut-brain interaction, 74

in order to better reflect their scientific basis. 2 FGIDs are diagnosed and classified using 75

standardised criteria, recommended by the Rome Foundation. Current approaches to 76

treatment target predominant gastrointestinal and psychological symptoms, rather than 77

identifying and addressing specific underlying pathophysiological mechanisms. Almost one-78

in-two people will meet criteria for an FGID at any given time, 3 and these conditions 79

frequently overlap. 4 More than two-thirds of people will have seen a doctor in the preceding 80

12 months, 40% use regular medication, and one-in-three will have had potentially 81

unnecessary abdominal surgery for their symptoms, such as hysterectomy or 82

cholecystectomy. 4 This, together with the fact that these conditions are costly to manage, 83

with an impact on quality of life of a similar magnitude to that of organic gastrointestinal 84

diseases, 4 highlights their fundamental importance to both healthcare systems and society. 85

Despite this, they are not a priority for research funding. 5 This is the first in a series of three 86


articles. The two accompanying articles deal with two of the most common FGIDs, IBS and 87

FD, in detail. 88

89

A PATIENT PERSPECTIVE 90

A diagnosis of an FGID has implications for the patient because of the stigma that 91

frequently accompanies it. These disorders lack structural “organic” features, so many 92

physicians view them as “second class” and attach negative attitudes or perceptions toward 93

patients with these conditions, 6 often considering them to have a psychiatric disorder. 7 This 94

can be damaging, both physically and emotionally, to the patient, 8 and lead to a sense of 95

stigma and shame. This, in turn, can inhibit the patient’s ability to express their thoughts and 96

feelings adequately to their providers, causing them to minimise the severity of their 97

symptoms and “gloss over” the impact on their quality of life. 8,9 Patients fear being seen as 98

“crazy”, and some choose instead to suffer needlessly without any medical interventions, 99

eventually giving up hope of regaining their quality of life or, alternatively, actually increase 100

their utilisation of healthcare in the search for answers. This process can cause patients to 101

reject the diagnosis, instead suspecting that the physician has “given up” rather than 102

continuing to seek the “real cause of the symptoms.” Even if they accept the diagnosis, they 103

may develop feelings of guilt and self-blame for having a condition not perceived by 104

physicians as “real.” 10 Half of all patients with FGIDs do not even inform their family 105

members and friends about the diagnosis, because of fear of being misunderstood or not 106

believed. 11 107

So, what can be done to change the perception of these disorders and these patients, 108

and provide more appropriate messaging and impactful care? We must begin first with the 109

clinicians who are looked upon to diagnose and heal. This is the role that physicians have 110


played throughout history. The frustration for many physicians is that FGIDs are not easily 111

“healed”, and often require constant symptom management, and therefore frequent visits and 112

follow-up. This can lead to frustration when the patient reports no improvement and can 113

contribute to physician burnout. 114

First, it is key that physicians know how to make a confident diagnosis of an FGID 115

using the symptom-based Rome criteria and communicate this diagnosis effectively, 116

providing rationale for the diagnosis and legitimising the disorder with clear, concise 117

communication. Using qualified language when giving a diagnosis is essential. A physician 118

should refrain from saying to a patient, “We think you have IBS” but instead phrase the 119

diagnosis as “You have IBS”. This use of qualified language increases patient acceptance, 120

reduces apprehension, and provides a framework to build upon for treatment 121

recommendations, medication adherence, and a positive patient-provider relationship. 12 122

Second, patients need to be given the proper education about their condition and have an 123

active role in the decision-making process for treatment. Patients respond better to clear, 124

concise education using images and diagrams to reinforce complex concepts such as the 125

brain-gut axis or pain gate control, preventing them from going to unqualified sources that 126

may contain inaccurate information. Finally, patients need to feel empowered in order to be 127

able to ask questions about anything they are unclear on, speak honestly about the severity of 128

their illness and its impact on their quality of life, and feel validated in their experiences. 129

When all of these elements are provided by a skilled clinician, both the patient and the 130

physician can find mutual satisfaction, positive outcomes, and a long-lasting relationship. 13 131

132

EPIDEMIOLOGY 133

The ability to appropriately classify patients with FGIDs is key, not only to facilitate 134

diagnosis and treatment, but also for research into their aetiology. Over the last 30 years, the 135


Rome Foundation, a committee of gastroenterologists and allied academics in the field of 136

gastrointestinal health, has created and updated standardised methods to diagnose and classify 137

FGIDs, based on a consensus of expert opinion, and with reference to current available 138

evidence. First proposed in 1990, the Rome diagnostic criteria define each condition 139

according to a particular cluster of patient-reported symptoms, sometimes with recourse to 140

limited investigations, and have undergone three subsequent revisions. There are 33 adult 141

FGIDs categorised by anatomical location (Table 1), each having validated symptom-based 142

criteria, which have been described in detail elsewhere. 14 The most recent iteration, Rome IV 143

published in 2016, advocate rethinking these conditions as disorders of gut-brain interaction, 144

acknowledging the complex interaction of biological, psychological, and social factors in 145

their pathogenesis. 2 This change also reflects the fact that the term “functional” is non-146

specific and, as a consequence, patients can feel stigmatised by a diagnostic label which is 147

viewed as less “legitimate”, or important, than that of an organic disease, despite often having 148

almost identical symptoms, which are equally genuine and troublesome. 2 However, some 149

diagnostic entities retain the term “functional” to identify those without physiological 150

markers or correlates. 151

A recent Rome Foundation global internet survey of 54,127 adults in the communities 152

of 26 countries reported that 32,112 (43%) people met criteria for at least one FGID. 3 These 153

individuals demonstrated increased healthcare utilisation, and lower quality of life than those 154

not meeting criteria. In one Swedish study, with 7 years of follow-up, only 232 (42%) of 547 155

respondents in the general population were symptom-free throughout. 15 Some of the 156

commonest FGIDs, as per Rome IV criteria, their estimated prevalence in the general 157

population in the Rome Foundation global survey, 3 and the confirmatory testing required to 158

make these diagnoses are described in Table 2. 16-21 IBS, FD, and functional constipation are 159

among the most prevalent FGIDs, and are a particular focus for researchers in the field. 160


However, other disorders, which are less well-understood, and lack evidence-based 161

treatments, such as rumination and functional dysphagia, are also more common than was 162

thought previously. 163

Women are generally more likely to suffer from FGIDs than men. 22-24 Indeed, the 164

Rome Foundation global survey demonstrated that 49% of women reported at least one 165

FGID, compared with 37% of men. 3 Recent epidemiological studies have demonstrated an 166

increased risk of both atopic and autoimmune diseases in FGIDs. 25,26 Smoking is also a risk 167

factor, 27 and extra-intestinal symptoms, such as fatigue or other chronic pain syndromes, 168

overlap more than would be expected by chance. 28,29 With respect to geography, studies 169

demonstrate consistently that, although FGIDs are present worldwide, there is variation in 170

prevalence rates between countries. 3,22-24,30,31 This variability may, in part, be due to 171

differences in methodology between studies. 31 It may, however, also reflect contrasts in 172

genetics, culture, lifestyle, and dietary traditions that exist between nations. 32,33 173

174

PATHOPHYSIOLOGY 175

By definition, no structural abnormalities explain FGIDs and, based on the 176

biopsychosocial model developed by Engel, 34 and adapted by Drossman, 35,36 they are 177

characterised as complex bidirectional dysregulation of brain-gut interaction, via the brain-178

gut axis, rather than diseases (Figure 1). Visceral hypersensitivity, abnormal gastrointestinal 179

motility, and psychological disturbances have been recognised to contribute to the 180

pathogenesis for decades, but more recently low-grade intestinal inflammation, increased 181

intestinal permeability, immune activation, and disturbances in the microbiome have been 182

identified, challenging the idea that structural changes are absent entirely. 37,38 183

An integrated model for pathogenesis of disease would help explain all of the known 184

phenomena encountered in FGIDs and, importantly, provide testable new insights into their 185


aetiology (Figure 2). 27,39 Importantly, the biopsychosocial model articulates illness as holistic 186

and multifactorial, and emphasises the existence of an intimate mind-body connection, 187

facilitated by bidirectional communication between the brain and the gut in FGIDs, which is 188

well-accepted. 34,35,40 Whatever the underlying aetiology and pathogenesis of FGIDs, central 189

nervous system processing of pain, and other gut signals, is required for the subjective patient 190

symptom experience. This is supported by data, including evidence that there are several 191

areas of abnormal brain activity associated with visceral hypersensitivity, as well as anxiety 192

and depression, in patients with FGIDs. 41,42 However, cause and effect cannot be 193

disentangled from these studies, and is not relevant when pathophysiology is understood in 194

terms of interacting systems. 195

Emerging data challenge the concept that brain-gut pathways act similarly in all 196

patients with FGIDs. Independent epidemiological studies suggest that in 50% of cases 197

FGIDs begin with psychological distress, followed later by gastrointestinal symptoms, 198

whereas in the other 50% of cases gut dysfunction occurs first, and psychological distress 199

follows later. 43-45 This has led to the hypothesis that a subset of patients have a disease 200

process that begins in, and is primarily driven by, the gastrointestinal tract, which later 201

induces systemic manifestations, including psychological dysfunction as an integral part of 202

the disease process. Further, likely microbial causes have been identified; H. pylori is a 203

recognised cause of FD, as the disorder remits long term in a small minority after successful 204

eradication of infection, 46 and following gastroenteritis new-onset IBS, FD, or both, may 205

occur and persist, 47,48 although gastroenteritis as a precipitant is identified by history in only 206

a minority of cases. 49,50 207

In further support of the importance of subtle underlying gastrointestinal pathology in 208

FGIDs, low-grade intestinal inflammation (characterised by eosinophils and/or mast cell 209

infiltration), increased intestinal permeability, an altered microbiome, and immune activation 210


(characterised by circulating homing small intestinal T-cells and a cytokine response) have 211

been identified in subsets of patients. 51-53 In turn, there is evidence that this low-grade 212

intestinal inflammatory process can alter neuronal structure and function, likely inducing 213

visceral hypersensitivity and gastrointestinal motor dysfunction. 54 Further, intestinal reflex 214

responses may then alter gut function more proximally, potentially inducing delayed gastric 215

emptying, impairing accommodation of the gastric fundus, or increasing transient lower 216

oesophageal sphincter relaxations, which may account for overlap between FGIDs. 55 217

Intestinal immune activation would be expected to be more prevalent in females, be 218

associated with a risk of atopic and autoimmune disease, and fluctuate over time, possibly 219

accounting for symptom variability, all of which have been observed in FD and IBS. 27 Most 220

patients with IBS and FD have meal-related symptoms; 56,57 dietary components, possibly in 221

some cases because of an aberrant interaction with the microbiome, may lead to antigen 222

presentation in the upper intestine, initiating immune activation and disease cascade. 58 In 223

other cases, a stress response driven centrally may be the primary disease process altering gut 224

function, via the hypothalamic pituitary adrenal axis, a brain-gut predominant disorder. 59 225

Adverse events in early life, possibly driving epigenetic changes, may account for symptom 226

chronicity and visceral hypersensitivity in a subgroup. 60 227

This gut-brain intestinal disease model is testable, and has treatment implications, 228

because it has the potential to identify casual pathways that can be interrupted. These include 229

removal of dietary antigens, specific manipulation of the microbiome, or targeted 230

immunotherapy and, in the future, may offer hope of cure rather than the use of purely 231

symptom-based therapies. 232

233

234

235


DIAGNOSIS 236

FGIDs share definable clinical features but, unlike IBD or other structurally-based 237

diseases, currently have no characteristic morphology or biomarkers that enable diagnosis. 238

Patients defined by these standardised criteria are homologous in their clinical features, thus 239

permitting investigators to enrol similar subjects into research, and clinicians to target 240

patients for a specific treatment. 241

Diagnosis of an FGID requires fulfilling symptom-based criteria and excluding, in a 242

cost-effective manner, other specific conditions having similar clinical presentations by 243

physical examination (including digital rectal exam), laboratory studies, and imaging (Table 244

2). For research purposes, it is essential to eliminate well-defined motility disorders, such as 245

chronic intestinal pseudo-obstruction or gastroparesis, or even other FGIDs. Therefore, for a 246

clinical trial in IBS, patients who meet criteria for IBS, but also have FD, would be excluded. 247

However, in clinical practice, it is well-accepted that motility disorders and other FGIDs 248

often co-exist; both diagnoses are recognised and treated. 249

The value of identifying other diagnoses, such as coeliac disease or IBD, which may 250

present with similar symptoms, is that they benefit from entirely different treatments. Yet, the 251

process of doing so requires good clinical judgment as there is risk in over-investigating. 13 252

Experienced clinicians can discern which patients need further evaluation. For example, a 253

college student attending a primary care clinic with an episode of abdominal cramps and 254

diarrhoea occurring before final examinations may receive minimal investigation, or no 255

investigations at all; the clinician will follow these symptoms expectantly. Conversely, an 256

older patient with similar symptoms that are increasing in severity over several months, with 257

accompanying weight loss, will require more evaluation and will likely undergo colonoscopy 258

and/or imaging studies. Also, the nature of the assessment will depend on the presenting 259


clinical features; predominant pain leads to a different set of investigations than chronic 260

diarrhoea or vomiting. 261

The best way to apply cost-effective and well-targeted diagnostic evaluations is to 262

consider specific clinical parameters initially. Factors that might lead to further assessment 263

include older age (e.g., colonoscopy after age 50), other co-morbidities, a shorter symptom 264

duration or a worsening severity and trajectory, no record of previous investigations, or the 265

presence of alarm symptoms or "red flags." The latter depend, to some degree, on anatomical 266

region, and the diagnosis under consideration, and include weight loss, haematemesis, 267

persistent vomiting, blood in the stool, family history of IBD or cancer, abnormal findings on 268

physical examination, or abnormal laboratory studies, such as anaemia. When the symptoms 269

are chronic, it is the development of new or changing clinical features, or alarm symptoms, 270

rather than increased reporting of symptoms, that determines the need for re-evaluation. One 271

method to address these parameters is through diagnostic algorithmic pathways, available 272

through the Rome Foundation. 61 As an example, Figure 3 demonstrates the recommended 273

evaluation pathway for patients presenting with constipation-type symptoms. 274

275

NATURAL HISTORY AND EFFECT 276

FGIDs are chronic conditions. Although symptoms fluctuate, and are often meal-277

related, 56,57 prevalence of symptom-reporting tends to remain the same, as the number of 278

people whose symptoms disappear are matched by the number who develop new-onset 279

symptoms. 62-64 The development of new-onset symptoms in those who were previously 280

asymptomatic may reflect bi-directional brain-gut pathways, with higher levels of anxiety and 281

depression associated with development of IBS and FD during follow-up. 44,45,65 However, in 282

longitudinal follow-up studies, among those who remain symptomatic, there is also transition 283

between different FGIDs. 64,66,67 Indeed, a Swedish study found that there was symptom 284


fluctuation in 40% to 60% of those reporting IBS, dyspepsia, gastro-oesophageal reflux 285

symptoms, or minor symptoms not meeting criteria for an FGID over a 7-year period. 15 286

Symptom overlap is also frequently observed, such that two or more FGIDs may co-exist, 68-287

70 as may other medically unexplained conditions, such as chronic fatigue syndrome, 71 or 288

fibromyalgia. 72 The prevalence of anxiety and depression increases with the number of co-289

existent FGIDs and with the frequency and severity of gastrointestinal symptoms. 73 Impaired 290

sleep is also common, 74,75 and again seems to increase with the number of overlapping 291

FGIDs. 74 292

Alarmingly, around one-third of patients with FGIDs will undergo unnecessary 293

surgery for their abdominal symptoms, including cholecystectomy and hysterectomy. 4 In one 294

survey of 51 (23%) of 223 patients with FD reported having surgery specifically to 295

investigate their symptoms, including exploratory operations. 76 A multivariate analysis 296

examining rates of surgery in patients with IBS, and adjusting for multiple confounders, 297

showed that having IBS was independently associated with three-fold higher rates of 298

cholecystectomy, two-fold higher rates of appendicectomy and hysterectomy, and 50% 299

higher rates of back surgery, compared with people without IBS. 77 Such procedures, coupled 300

with the fact that two-thirds of patients have seen a doctor in the preceding 12 months and 301

40% are taking medication for their symptoms, 4 add to the considerable healthcare costs of 302

managing FGIDs. 76,78-80 Although functional constipation has been associated with an 303

increased mortality risk, 81,82 this does not appear to be the case for other FGIDs. However, 304

morbidity is striking. Patients report negative effects on their ability to work, with high rates 305

of absenteeism and presenteeism, 83 and their ability to socialise. 80 The detrimental impact on 306

health-related quality of life is, therefore, substantial. 3,80 307

308

309


MANAGEMENT 310

The general principles of treatment are based on a biopsychosocial understanding, 36 311

and relate to dysregulation of the brain-gut axis. The FGIDs are defined by any combination 312

of motility disturbance, visceral hypersensitivity, altered mucosal and immune function, 313

altered gut microbiota, and altered central nervous system processing. 16 Thus, patients 314

meeting Rome IV criteria for an FGID may have protean symptom features influenced by 315

various combinations of these factors. So for example, a patient meeting IBS criteria may 316

have bloating related to maldigestion of dietary constituents, such as fermentable oligo-, di-, 317

or mono-saccharides, and polyols (FODMAPs), pain and diarrhoea related to visceral 318

hypersensitivity, altered mucosal immune dysregulation following a bacterial infection (post-319

infection IBS), or anxiety and pain due to central pain dysregulation, and associated with 320

post-traumatic stress disorder following sexual or physical trauma. Since the clinical profile 321

and severity may change over time, the discerning clinician needs to identify which of these 322

factors alone, or in combination, are targets for treatment. There are several principles to 323

consider when initiating treatment, which are considered below. 324

325

The Patient-provider Relationship. 326

It is well-established that an effective patient-provider relationship improves patient 327

and provider satisfaction, adherence to treatment, symptom reduction, and improved clinical 328

outcomes. 13,84,85 Table 3 provides general guidelines to establish and optimise this. 84 329

330

The Symptom Profile 331

The type of symptoms, their location, and the physiological determinants will all 332

influence treatment. Simple inexpensive treatments, such as laxatives or anti-diarrhoeals, will 333

be sufficient for some patients, although the evidence base for these is limited. Trial-based 334


and network meta-analyses demonstrate that, for functional constipation or IBS with 335

constipation, drugs like linaclotide or lubiprostone acting as secretagogues, via intestinal ion 336

channels, or prokinetics, such as prucalopride or tegaserod, via 5-hydroxytryptamine (5-HT) 337

receptors, are efficacious, 86-88 whereas for diarrhoea in IBS, rifaximin, a minimally absorbed 338

antibiotic, alosetron or ondansetron, which are 5HT3 receptor antagonists, or the mixed 339

opioid receptor drug eluxadoline, are beneficial . 89-91 However, if the accompanying 340

abdominal pain is severe, treatment will include an antidepressant or a CNS targeted 341

medication, termed central neuromodulators, 92,93 and, if localised to the rectum (e.g., levator 342

ani syndrome), may also be treated by biofeedback. 21 The clinician needs to determine which 343

symptom features are dominant, and which treatment(s) are most likely to lead to 344

improvement. 345

346

Psychosocial Features 347

The brain-gut axis is the basis for a bidirectional relationship, where gastrointestinal 348

symptoms influence psychosocial state, and vice versa. Thus, chronic pain, nausea, or 349

vomiting can lead to anxiety or depression, as modified by early experiences, coping, and 350

social and family influences. Conversely, psychosocial difficulties, including co-morbid 351

anxiety, depression, a significant loss, or sexual or physical trauma history, influences pain 352

threshold and gastrointestinal motility. This relationship justifies the use of gastrointestinal 353

behavioural treatments such as cognitive-behavioural therapy or hypnotherapy., 94 354

Although psychosocial co-morbidities may determine referral for gastrointestinal 355

behavioural intervention, it is also recognised that it is the patient's awareness of the value of 356

the treatment and the motivation to engage that determines success. 95 The best candidates for 357

gastrointestinal behavioural treatments understand the nature of gut-brain disorders, are open 358

to behavioural change to alleviate symptoms, can make connections between times of stress 359


and anxiety and symptoms, and have the time to participate in the treatment. Patients with 360

severe psychopathology or personality disorder, who have little insight into the gut-brain 361

interaction, who are fixated on a "cure," or who are unable or unwilling to commit to 362

treatment are unlikely to benefit. 94 363

364

Symptom Severity 365

Severity is a biopsychosocial composite of patient-reported gastrointestinal and extra-366

intestinal symptoms, the degree of pain, disability, psychosocial impairments, illness-related 367

perceptions and behaviours, and health-related quality of life. 96 It is operative when making 368

treatment decisions. For example, a patient having infrequent low-grade abdominal pain with 369

no other symptoms, and no psychological distress is unlikely to seek healthcare, and would 370

be classified as mild, and not treated. Conversely, a patient having severe abdominal pain, 371

along with fibromyalgia and migraine headaches, who is unable to work, depressed, and 372

frequently seeks healthcare, or is hospitalised, would be considered severe, and treated with 373

behavioural and multiple medical treatments. Table 4 provides guidelines developed by a 374

Rome Foundation working team to help categorise severity for FGIDs. 96 375

376

In summary, treatment of FGIDs requires an effective patient-provider relationship 377

and a multimodal approach that incorporates the nature of the symptoms, their severity, the 378

presence of psychosocial co-morbidities and, in combination, their impact. The multi-379

dimensional clinical profile, which has been proposed by the Rome Foundation, takes these 380

factors into consideration, in order to help the clinician provide care that is targeted to the 381

personal needs of the patient. 97,98 The five components of this include: 382

A. Categorical diagnosis (the symptom-based criteria) 383


B. Clinical modifier (e.g., IBS with constipation, diarrhoea, or mixed bowel habits, post-384

infection aetiology, FODMAP sensitivity) 385

C. Impact (mild, moderate, severe) 386

D. Psychosocial modifier (e.g., psychological diagnosis, loss, trauma history,) 387

E. Physiological dysfunction and biomarkers (where available) 388

Although currently this model has heuristic value and is being promoted in clinical education, 389

98 future studies are needed to provide evidential support. 390

391

CONCLUSIONS 392

FGIDs are extremely prevalent, affecting almost one-in-two people at some point in 393

their lives. Due to healthcare seeking, excess surgeries, medications, and their effects on 394

quality of life, psychological health, work, and social functioning they have a substantial 395

impact not only on the lives of sufferers, but also society as a whole. The pathophysiology is 396

complex, but the biopsychosocial model provides a framework to articulate this. Novel, 397

testable, models may further improve our understanding. Although treatment remains 398

symptom-based, it is recognised increasingly that there is a need to enhance the patient-399

provider relationship, and that this should be multimodal, to maximise chances of success. In 400

the future, treatment approaches are likely to become more personalised based not only on 401

symptoms, but also underlying pathophysiology and psychology. 402

403

Contributors 404

CJB, DAD, NJT, JR, and ACF did the literature search, wrote the manuscript, and drafted the 405

figures. ACF and DAD revised the initial manuscript. All authors critically revised 406

subsequent versions of the manuscript and approved the final version of the manuscript. 407

408


Declaration of Interests 409

CJB has no conflicts of interest. DAD is President Emeritus and Chief of Operations of the 410

Rome Foundation. NJT reports grants from Abbott Pharmaceuticals, grants from 411

Commonwealth Diagnostics , non-financial support from HVN National Science Challenge 412

NZ, grants and personal fees from GI therapies, grants from Viscera USA , personal fees 413

from Adelphi values, personal fees from Allergens PLC , personal fees from Takeda, 414

personal fees from Ampligent, personal fees from Progenity Inc , personal fees from Sanofi-415

aventis, personal fees from IM Health Sciences, personal fees from Napo Pharmaceutical, 416

personal fees from Outpost Medicine, personal fees from Samsung Bioepis, personal fees 417

from Synergy, personal fees from Theravance, personal fees from Yuhan, grants from 418

Prometheus (IBS), grants from Pfizer, grants from Rome Foundation , grants from Salix , 419

personal fees from Aviro Health (Digestive health) , personal fees from ARENA 420

Pharmaceuticals , personal fees from Anatara Life Sciences, personal fees from Allakos, 421

personal fees from Censa, personal fees from Cadila Pharmaceuticals , personal fees from 422

Danone, personal fees from Dr. Reddy's Laboratories , personal fees from Planet Innovation , 423

personal fees from twoXAR, personal fees from Theravance, personal fees from Dr Falk, 424

outside the submitted work. In addition, NJT has a patent Biomarkers of IBS licensed, a 425

patent Licensing Questionnaires Talley Bowel Disease Questionnaire licensed to 426

Mayo/Talley, a patent Nestec European Patent licensed, and a patent Singapore Provisional 427

PatentÐu8220“Microbiota Modulation Of BDNF Tissue Repair Pathway” issued. JR has no 428

conflicts of interest. ACF has no conflicts of interest. 429

430


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694

695


Table 1. Rome IV Adult Functional Gastrointestinal Disorders (Disorders of Gut-Brain 696

Interaction). 697

A. Oesophageal Disorders

A1. Functional chest pain

A2. Functional heartburn

A3. Reflux hypersensitivity

A4. Globus

A5. Functional dysphagia

B. Gastroduodenal Disorders

B1. Functional dyspepsia

B1a. Postprandial distress syndrome

B1b. Epigastric pain syndrome

B2. Belching disorders

B2a. Excessive supragastric belching

B2b. Excessive gastric belching

B3. Nausea and vomiting disorders

B3a. Chronic nausea vomiting syndrome

B3b. Cyclic vomiting syndrome

B3c. Cannabinoid hyperemesis syndrome

B4. Rumination syndrome

C. Bowel Disorders

C1. Irritable bowel syndrome

C1a. IBS with predominant constipation

C1b. IBS with predominant diarrhoea

C1c. IBS with mixed bowel habits

C1d. IBS unclassified

C2. Functional constipation

C3. Functional diarrhoea

C4. Functional abdominal bloating or

distension

C5. Unspecified functional bowel disorder

C6. Opioid-induced constipation

D. Centrally Mediated Disorders of Gastrointestinal Pain

D1. Centrally-mediated abdominal pain

syndrome

D2. Narcotic bowel syndrome or opioid-

induced gastrointestinal hyperalgesia

E. Gallbladder and Sphincter of Oddi Disorders

E1. Biliary pain

E1a. Functional gallbladder disorder

E1b. Functional biliary sphincter of Oddi

disorder

E2. Functional pancreatic sphincter of Oddi

disorder

F. Anorectal Disorders

F1. Faecal incontinence

F2. Functional anorectal pain

F2a. Levator ani syndrome

F2b. Unspecified functional anorectal

pain

F2c. Proctalgia fugax

F3. Functional defaecation disorders

F3a. Inadequate defaecatory propulsion

F3b. Dyssynergic defaecation

698


Table 2. Definitions of Some of the Commonest Rome IV Adult Functional Gastrointestinal Disorders, Population Prevalence,

and Confirmatory Tests Required.

Diagnosis Definition Prevalence*

(%) 3

Confirmatory tests required† 18-21

Functional dysphagia A sensation of abnormal food bolus transit through the

oesophagus in the absence of structural, motor, or mucosal

abnormalities

3.2 Endoscopy and biopsies, barium swallow, and

high-resolution oesophageal manometry

Functional heartburn Retrosternal burning, discomfort, or pain, which is refractory to

optimal acid suppression therapy, in the absence of gastro-

oesophageal reflux, histopathological mucosal abnormalities,

major motor disorders, or structural abnormalities

1.1 Endoscopy and biopsies, and 24-hour pH and

impedance studies

Functional chest pain Recurrent, unexplained, retrosternal chest pain of presumed

oesophageal origin, which is different from heartburn, and not

explained by reflux disease, or mucosal, or motor abnormalities

1.4 Cardiology work-up, endoscopy and biopsies, and

24-hour pH and impedance studies


Functional dyspepsia Characterised by one or more of the following: postprandial

fullness, early satiety, epigastric pain, or epigastric burning, that

are unexplained after routine clinical investigation

7.2 Endoscopy and biopsies if alarm symptoms

present

Rumination syndrome Repetitive, effortless regurgitation of recently ingested food into

the mouth, followed by either re-chewing and re-swallowing, or

expulsion of the food bolus

2.8 High-resolution oesophageal manometry

Cyclic vomiting

syndrome

Stereotypical episodes of vomiting, with an acute onset, and

lasting less than 1 week, with the absence of vomiting between

episodes

1.2 History is usually typical, but if atypical features

consider endoscopy, computed tomography of the

brain, and porphyria screen

Functional

constipation

Symptoms of difficult, infrequent, or incomplete defaecation,

not meeting criteria for irritable bowel syndrome and, although

abdominal pain/bloating may be present, they are not

predominant symptoms

11.7 Full blood count, thyroid functions tests, and

serum calcium, with colonoscopy only if >50

years

Irritable bowel

syndrome

Recurrent abdominal pain, at least 1 day per week, associated

with defaecation or a change in bowel habits

4.1 Full blood count, C-reactive protein, coeliac

serology, and faecal calprotectin (if diarrhoea

present), with colonoscopy only if >50 years or

alarm symptoms or atypical features present


Functional diarrhoea Recurrent passage of loose or watery stools, not meeting criteria

for irritable bowel syndrome and, although abdominal

pain/bloating may be present, they are not predominant

symptoms

4.7 Full blood count, C-reactive protein, thyroid

function tests, coeliac serology, faecal

calprotectin and elastase, with colonoscopy only

if >50 years or alarm symptoms present

Functional abdominal

bloating/distension

Subjective symptoms of abdominal fullness, pressure, or a

sensation of trapped gas (bloating); an objective measurable

increase in abdominal girth (distension); not meeting criteria for

an alternative functional bowel disorder, although mild

abdominal pain or minor changes in bowel habit may co-exist

3.5 Full blood count, coeliac serology, and CA-125

(in female patients only)

Functional bowel

disorder, unspecified

Bowel symptoms, not attributable to an organic aetiology, and

not meeting diagnostic criteria for irritable bowel syndrome,

functional constipation, functional diarrhoea, or functional

abdominal bloating/distension

11.0 As this is a diagnosis reached in a patient not

meeting criteria for functional constipation, IBS,

functional diarrhoea, or functional abdominal

bloating/distension, investigations are as specified

for these disorders

Proctalgia fugax A sudden, severe pain in the rectal area, lasting for a few

seconds to several minutes, and then disappearing completely

5.9 Anorectal manometry and magnetic resonance

imaging of the pelvis

*The total proportion of people reporting symptoms compatible with at least one FGID in this Rome Foundation global burden of illness study was

42.7%, 3 but the combined prevalence in the table adds up to >50%, because FGIDs frequently overlap with each other. 4 This increases the negative


impact on quality of life and psychological health, and increases the likelihood of consultation, need for medical therapy, and potential for unnecessary

surgery. 4

†Many of these investigations are only available in secondary care. The clinician in primary care is more likely to make a diagnosis on clinical grounds

and treat or refer if there is diagnostic uncertainty.


Table 3. Guidelines for Establishing an Effective Patient-provider Relationship. 13

1. Improve patient satisfaction and

engagement with the patient.

Satisfaction relates to the patient's perception of the provider's humaneness, technical competence,

interest in psychosocial factors, and providing relevant medical information. Engagement relies on

nonverbal communication including good eye contact, affirmative nods, gentle tone of voice, close

interpersonal distance, and creation of a partner-like interaction.

2. Obtain the history through a non-directive,

non-judgmental, patient-centred interview.

This process involves active listening and employing questions based on the patient's thoughts,

feelings, and experiences, rather than on using a personal or pre-set list of questions.

3. Determine the immediate reason for the

patient's visit and evaluate the patient's

verbal and non-verbal communication.

“What led you to see me at this time?”

Reasons may include: 1) new or exacerbating factors (dietary change, concurrent medical disorder, side

effects of new medication); 2) personal concern about a severe disease (e.g., recent family death); 3)

personal or family stressors (e.g., recent or anniversary of a death or other major loss, abuse event or

history); 4) worsening or development of psychiatric co-morbidity (e.g., depression or anxiety); 5)

impairment in daily function (recent inability to work or socialise), or 6) a "hidden agenda" such as

narcotic or laxative abuse, pending litigation, or disability claims.

4. Conduct a careful physical examination

and cost-efficient investigation.

A well-conducted physical examination has therapeutic value. 99

5. Determine the patient's understanding of

the illness and concerns.

“What do you think is causing your symptoms?" or "What concerns or worries do you have about your

condition?”


6. Elicit the patient's understanding of the

symptoms ("illness schema") and provide

an explanation that considers the patient's

beliefs.

“I understand you believe you have an undiagnosed infection. We understand the infection is gone, but

your nerves have been affected by it so that it feels as though the infection is still there, like a 'phantom

limb'.”

7. Identify and respond realistically to the

patient's expectations for improvement.

“How do you feel I can be helpful to you?”

8. When possible, provide a link between

stressors and symptoms that are consistent

with the patient's beliefs.

Many patients are unable to associate stressors with illness. Still, most will understand the stress of the

illness on their emotional state.

“I understand you don't see stress as causing your pain, but you've mentioned how severe and disabling

your pain is. How much do you think that is causing you emotional distress?”

9. Set consistent limits. “I appreciate how bad the pain must be, but narcotic medication is not indicated because it can be

harmful.”

10. Involve the patient in the treatment. “Let me suggest some treatments for you to consider.”

11. Make recommendations consistent with

patient interests.

“Neuromodulators can be used for depression, but they also are used to 'turn down' the pain, and pain

benefit occurs in doses lower than those used for depression.”

12. Help establish an ongoing relationship with

you, or in association with a primary care

provider.

“Whatever the result of this treatment, I'm prepared to consider other options, and I will continue to

work with you through this.”


Table 4. Clinical Profile for Severity in Functional Gastrointestinal Disorders. 16,96

Clinical Feature Mild Moderate Severe

Estimated prevalence 40% 35% 25%

Symptom severity score

as a psychometric

correlate*

Low Medium High

Physiological factors Primarily gastrointestinal

dysfunction

Gastrointestinal

dysfunction and CNS

pain dysregulation

Primarily CNS pain

dysregulation

Psychosocial difficulties None or mild

psychological distress

Moderate psychological

distress

Severe psychological

distress, catastrophising,

abuse history

Abdominal pain Mild, intermittent Moderate, frequent Severe, very frequent or

constant

Number of extra-

intestinal symptoms

Low (1–3) Medium (4–6) High (7 or more)

Health-related quality of

life

Good Fair Poor

Healthcare utilisation 0–1 time per year 2–4 times per year 5 or more times per year

Activity restriction Occasional (0–15 days) More often (15–50 days) Frequent or constant

(more than 50 days)

Work disability <5% 6 to 10% 11% or greater

*For example: low, an IBS-symptom severity score (IBS-SSS) of 75-175; medium, an IBS-

SSS of 176-300; high, an IBS-SSS of >300.


Figure 1. A Biopsychosocial Model of Functional Gastrointestinal Disorders.

Adapted from van Oudenhove et al. 35

Figure 2. Intestinal Immune Activation Model of Functional Gastrointestinal Disorders.

It is hypothesised that, in a genetically primed host, environmental factors induce

immune activation. Antigen presentation of luminal antigens, such as pathogens or food

peptides, to T cells drives maturation of naïve T cells to T-helper 2 cells. The release of

associated cytokines (IL-4, IL-5, and IL-13) promotes the activation and recruitment of

eosinophils, B cells, and mast cells. In addition to the traditional T-helper 2 pathway,

secretion of IL-23 from antigen-presenting cells, such as dendritic cells, B cells, and

macrophages, promotes Th17 helper cell differentiation. The production of GM-CSF

from Th17 helper cells further drives eosinophil recruitment. Degranulation of mast

cells and eosinophils results in the release of inflammatory mediators, which can

damage the intestinal barrier, and stimulate and damage enteric nerve fibres, to induce

visceral hypersensitivity and motility disturbances, resulting in gastrointestinal

symptoms. α4β7 gut homing T cells are a marker of intestinal inflammation in both

functional dyspepsia and irritable bowel syndrome, and correlate with delayed gastric

emptying. Duodenal motor dysfunction may also impair duodenal acid clearance,

inducing intestino-gastric reflex responses that impair accommodation of the gastric

fundus, and increase transient lower oesophageal sphincter relaxations, leading to

gastro-oesophageal reflux. Signalling cascades, leading to further cytokine release, may

result in extra-intestinal symptoms, such as anxiety and fatigue. The site and extent of

intestinal immune activation may define the phenotype (proximal intestinal involvement

functional heartburn or functional dyspepsia; more distal involvement irritable bowel

syndrome, functional constipation, or functional diarrhoea). Adapted from Talley and

Talley. 39 27


Figure 3. Diagnostic Algorithm Pathway for a Patient Presenting with Uninvestigated

Constipation-type Symptoms. 61

*A recent change in bowel habit, unintentional weight loss (>10% of ideal body weight),

nocturnal symptoms, a family history of colorectal cancer, rectal bleeding (not caused

by haemorrhoids or anal fissures), or age >50 years.

The pathways have been validated and standardised by the Rome Foundation. Purple

represents a clinical state (diagnosis), gold represents a decision box (entry path with

“yes” and “no” exit paths), and green represents an action box (diagnostic test or

therapeutic action required).

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